Cytokine signaling by IL10 and IFN-gamma plays crucial roles in inflammation, cancer growth and autoimmune diseases. IFN-gamma, produced primarily by natural killer cells, is associated with anti-virus, pro-apoptotic tumor functions. However, recent studies have shown that aberrant IFN-gamma expression is associated with a number of autoimmune and auto-inflammatory diseases, liver cancers, papillomas, and breast cancers. In addition, IFN-gamma signaling on T cells is a critical step in initiating an adaptive immune response in graft-versus-host-disease (GVHD). GVHD remains one of the most prevalent causes of morbidity and mortality after bone marrow transplantations in leukemia patients.
IL10 is an anti-inflammatory cytokine and is involved in immune regulation and inflammation. It controls the immune response, preventing hosts from exaggerated inflammatory and immune reactions. However, it also disarms innate as well as adaptive responses, creating favorable conditions for the persistence of pathogens. Epstein-Barr virus, Orf virus, bovine papular stomatitis virus, lumpy skin disease virus and cytomegaloviruses encode variants of IL10 that allow them to escape eradication by immune system. In addition, several pathogens, like HIV-1, Dengue virus, influenza virus, measles virus, and West Nile virus are capable of stimulating IL10 production, which leads to impaired immune response. Thus, inhibition of IL10 activity may lead to a new way of treating infectious diseases, autoimmune diseases, and cancer. Blockade of IL10 was also suggested to be an effective adjuvant to specifically enhance CD4 T cell immunity and protection following vaccination.
Currently, there are no selective inhibitors of cytokines signaling, except antibodies. Thus, there remains a desire for selective inhibitors, particularly inhibitors of IFN-gamma and IL10 signaling.